Publications by authors named "Oliver Soehnlein"

171 Publications

TIMP-1 triggers neutrophil extracellular trap formation in pancreatic cancer.

Cancer Res 2021 May 3. Epub 2021 May 3.

Institut fur Molekulare Immunologie und Experimentelle Onkologie, Klinikum rechts der Isar Technischen Universitat Munchen

Tumor-derived protein tissue inhibitor of metalloproteinases-1 (TIMP-1) correlates with poor prognosis in many cancers, including highly lethal pancreatic ductal adenocarcinoma (PDAC). The non-canonical signaling activity of TIMP-1 is emerging as one basis for its contribution to cancer progression. However, TIMP-1-triggered progression-related biological processes are largely unknown. Formation of neutrophil extracellular traps (NET) in the tumor microenvironment is known to drive progression of PDAC, but factors or molecular mechanisms initiating NET formation in PDAC remain elusive. In this study, gene set enrichment analysis of a human PDAC proteome dataset revealed that TIMP-1 protein expression most prominently correlates with neutrophil activation in patient-derived tumor tissues. TIMP-1 directly triggered formation of NETs in primary human neutrophils, which was dependent on the interaction of TIMP-1 with its receptor CD63 and subsequent ERK signaling. In genetically engineered PDAC-bearing mice, TIMP-1 significantly contributed to NET formation in tumors, and abrogation of TIMP-1 or NETs prolonged survival. In patient-derived PDAC tumors, NETs predominantly colocalized with areas of elevated TIMP-1 expression. Furthermore, TIMP-1 plasma levels correlated with DNA-bound myeloperoxidase, a NET marker, in the blood of PDAC patients. A combination of plasma levels of TIMP-1 and NETs with the clinically established marker CA19-9 allowed improved identification of prognostically distinct PDAC patient subgroups. These observations may have a broader impact, since elevated systemic levels of TIMP-1 are associated with the progression of a wide range of neutrophil-involved inflammatory diseases.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-4125DOI Listing
May 2021

The voltage-gated potassium channel KV1.3 regulates neutrophil recruitment during inflammation.

Cardiovasc Res 2021 Apr 21. Epub 2021 Apr 21.

Walter Brendel Centre of Experimental Medicine, Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, 82152, Planegg-Martinsried, Germany.

Aims: Neutrophil trafficking within the vasculature strongly relies on intracellular calcium signaling. Sustained Ca2+ influx into the cell requires a compensatory efflux of potassium to maintain membrane potential. Here, we aimed to investigate whether the voltage-gated potassium channel KV1.3 regulates neutrophil function during the acute inflammatory process by affecting sustained Ca2+ signaling.

Methods And Results: Using in vitro assays and electrophysiological techniques, we show that KV1.3 is functionally expressed in human neutrophils regulating sustained store operated Ca2+ entry (SOCE) through membrane potential stabilizing K+ efflux. Inhibition of KV1.3 on neutrophils by the specific inhibitor 5-(4-Phenoxybutoxy)psoralen (PAP-1) impaired intracellular Ca2+ signaling, thereby preventing cellular spreading, adhesion strengthening and appropriate crawling under flow conditions in vitro. Using intravital microscopy, we show that pharmacological blockade or genetic deletion of KV1.3 in mice decreased neutrophil adhesion in a blood flow dependent fashion in inflamed cremaster muscle venules. Furthermore, we identified KV1.3 as a critical component for neutrophil extravasation into the inflamed peritoneal cavity. Finally, we also revealed impaired phagocytosis of E.coli particles by neutrophils in the absence of KV1.3.

Conclusion: We show that the voltage gated potassium channel KV1.3 is critical for Ca2+ signaling and neutrophil trafficking during acute inflammatory processes. Our findings do not only provide evidence for a role of KV1.3 for sustained calcium signaling in neutrophils affecting key functions of these cells, they also open up new therapeutic approaches to treat inflammatory disorders characterized by overwhelming neutrophil infiltration.

Translational Perspective: Neutrophils exert important immune functions during tissue injury or bacterial infection through leaving the vasculature and extravasate into affected tissues. Conversely, neutrophils trigger the pathogenesis of acute and chronic inflammatory disorders and are involved in the development and maintenance of various autoimmune diseases. Within this study, we show that the voltage-gated potassium channel KV1.3 is functionally expressed on neutrophils and affects calcium signaling thereby regulating neutrophil effector functions during immune responses. Hence, KV1.3 represents an interesting potential new target to treat unwanted excessive neutrophil invasion in various disorders ranging from autoinflammatory disorders to ischemic tissue injury.
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http://dx.doi.org/10.1093/cvr/cvab133DOI Listing
April 2021

Extracellular histones are a target in myocardial ischaemia reperfusion injury.

Cardiovasc Res 2021 Apr 20. Epub 2021 Apr 20.

The Hatter Cardiovascular Institute, University College London, WC1E 6HX, United Kingdom.

Acute myocardial infarction causes lethal cardiomyocyte injury during ischaemia and reperfusion (I/R). Histones have been described as important Danger Associated Molecular Proteins (DAMPs) in sepsis. Aims The objective of this study was to establish whether extracellular histone release contributes to myocardial infarction. Methods and results Isolated, perfused rat hearts were subject to I/R. Nucleosomes and histone H4 release was detected early during reperfusion. Sodium-β-O-Methyl cellobioside sulfate (mCBS), a newly developed histone-neutralising compound, significantly reduced infarct size whilst also reducing the detectable levels of histones. Histones were directly toxic to primary adult rat cardiomyocytes in vitro. This was prevented by mCBS, or HIPe, a recently described, histone-H4 neutralizing peptide, but not by an inhibitor of TLR4, a receptor previously reported to be involved in DAMP-mediated cytotoxicity. Furthermore, TLR4-reporter HEK293 cells revealed that cytotoxicity of histone H4 was independent of TLR4 and NF-κB. In an in vivo rat model of I/R, HIPe significantly reduced infarct size. Conclusion Histones released from the myocardium are cytotoxic to cardiomyocytes, via a TLR4-independent mechanism. The targeting of extracellular histones provides a novel opportunity to limit cardiomyocyte death during I/R injury of the myocardium. Translational perspective Acute myocardial infarction causes lethal cardiomyocyte injury during ischaemia and reperfusion (I/R). New approaches are needed to prevent cardiomyocyte injury and limit final infarct size. We show that histones released from damaged cells, and histone-H4 in particular, causes rapid cardiomyocyte death during I/R. mCBS, a compounds targeting histones non-specifically, was cardioprotective in ex vivo rat hearts, while HIPe, a targeting histone H4 specifically, was cardioprotective in an in vivo rat model. HIPe may have potential as a therapeutic agent in the setting of acute myocardial infarction.
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http://dx.doi.org/10.1093/cvr/cvab139DOI Listing
April 2021

Monocyte-Chemoattractant Protein-1 Levels in Human Atherosclerotic Lesions Associate With Plaque Vulnerability.

Arterioscler Thromb Vasc Biol 2021 04 8:ATVBAHA121316091. Epub 2021 Apr 8.

Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Germany (M.K.G., Y.A., M.D.).

Objective: To determine whether MCP-1 (monocyte chemoattractant protein 1) levels in human atherosclerotic plaques associate with plaque vulnerability features. Approach and Results: We measured MCP-1 levels in human atherosclerotic plaque samples from 1199 patients in the Athero-EXPRESS Biobank who underwent endarterectomy for treatment of carotid stenosis. We explored associations with histopathologic and molecular features of plaque vulnerability, clinical plaque manifestations, and vascular events up to 3 years after endarterectomy. Following adjustments for age, sex, and vascular risk factors, MCP-1 plaque levels were associated with histopathologic markers of plaque vulnerability (large lipid core, low collagen content, high macrophage burden, low smooth muscle cell burden, intraplaque hemorrhage) and with a composite vulnerability index (range 0-5, β per SD increment in MCP-1, 0.42 [95% CI, 0.30-0.53], =5.4×10). We further found significant associations with higher plaque levels of other chemokines and proinflammatory molecules and markers of neovascularization and matrix turnover. When exploring clinical plaque instability, MCP-1 plaque levels were higher among individuals with symptomatic plaques as compared with those with asymptomatic plaques (odds ratio per SD increment in MCP-1, 1.36 [95% CI, 1.09-1.69]). MCP-1 levels were further associated with a higher risk of periprocedural major adverse vascular events and strokes occurring in the first 30 days after plaque removal.

Conclusions: Higher MCP-1 plaque levels are associated with histopathologic, molecular, and clinical hallmarks of plaque vulnerability in individuals undergoing carotid endarterectomy. Our findings highlight a role of MCP-1 in clinical plaque instability in humans and complement previous epidemiological, genetic, and experimental studies supporting the translational perspective of targeting MCP-1 signaling in atherosclerosis.
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http://dx.doi.org/10.1161/ATVBAHA.121.316091DOI Listing
April 2021

The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis.

Nature 2021 Apr 17;592(7853):296-301. Epub 2021 Mar 17.

Division of Molecular Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.

Clonal haematopoiesis, which is highly prevalent in older individuals, arises from somatic mutations that endow a proliferative advantage to haematopoietic cells. Clonal haematopoiesis increases the risk of myocardial infarction and stroke independently of traditional risk factors. Among the common genetic variants that give rise to clonal haematopoiesis, the JAK2 (JAK2) mutation, which increases JAK-STAT signalling, occurs at a younger age and imparts the strongest risk of premature coronary heart disease. Here we show increased proliferation of macrophages and prominent formation of necrotic cores in atherosclerotic lesions in mice that express Jak2 selectively in macrophages, and in chimeric mice that model clonal haematopoiesis. Deletion of the essential inflammasome components caspase 1 and 11, or of the pyroptosis executioner gasdermin D, reversed these adverse changes. Jak2 lesions showed increased expression of AIM2, oxidative DNA damage and DNA replication stress, and Aim2 deficiency reduced atherosclerosis. Single-cell RNA sequencing analysis of Jak2 lesions revealed a landscape that was enriched for inflammatory myeloid cells, which were suppressed by deletion of Gsdmd. Inhibition of the inflammasome product interleukin-1β reduced macrophage proliferation and necrotic formation while increasing the thickness of fibrous caps, indicating that it stabilized plaques. Our findings suggest that increased proliferation and glycolytic metabolism in Jak2 macrophages lead to DNA replication stress and activation of the AIM2 inflammasome, thereby aggravating atherosclerosis. Precise application of therapies that target interleukin-1β or specific inflammasomes according to clonal haematopoiesis status could substantially reduce cardiovascular risk.
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http://dx.doi.org/10.1038/s41586-021-03341-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038646PMC
April 2021

Structure-based peptide design targeting intrinsically disordered proteins: Novel histone H4 and H2A peptidic inhibitors.

Comput Struct Biotechnol J 2021 21;19:934-948. Epub 2021 Jan 21.

Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.

A growing body of research has demonstrated that targeting intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs) is feasible and represents a new trending strategy in drug discovery. However, the number of inhibitors targeting IDPs/IDPRs is increasing slowly due to limitations of the methods that can be used to accelerate the discovery process. We have applied structure-based methods to successfully develop the first peptidic inhibitor ( - istone nhibitory ptide) that targets histone H4 that are released from NETs (Neutrophil Extracellular Traps). HIPe binds stably to the disordered N-terminal tail of histone H4, thereby preventing histone H4-induced cell death. Recently, by utilisation of the same state-of-the-art approaches, we have developed a novel peptidic inhibitor ( - yclical istone H2A nterference eptide) that binds to NET-resident histone H2A, which results in a blockade of monocyte adhesion and consequently reduction in atheroprogression. Here, we present comprehensive details on the computational methods utilised to design and develop HIPe and CHIP. We have exploited protein-protein complexes as starting structures for rational peptide design and then applied binding free energy methods to predict and prioritise binding strength of the designed peptides with histone H4 and H2A. By doing this way, we have modelled only around 20 peptides and from these were able to select 4-5 peptides, from a total of more than a trillion candidate peptides, for functional characterisation in different experiments. The developed computational protocols are generic and can be widely used to design and develop novel inhibitors for other disordered proteins.
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http://dx.doi.org/10.1016/j.csbj.2021.01.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856395PMC
January 2021

Synthesis and evaluation of novel cyclopentane urea FPR2 agonists and their potential application in the treatment of cardiovascular inflammation.

Eur J Med Chem 2021 Mar 16;214:113194. Epub 2021 Jan 16.

LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, UK.

The discovery of natural specialized pro-resolving mediators and their corresponding receptors, such as formyl peptide receptor 2 (FPR2), indicated that resolution of inflammation (RoI) is an active process which could be harnessed for innovative approaches to tame pathologies with underlying chronic inflammation. In this work, homology modelling, molecular docking and pharmacophore studies were deployed to assist the rationalization of the structure-activity relationships of known FPR2 agonists. The developed pharmacophore hypothesis was then used in parallel with the homology model for the design of novel ligand structures and in virtual screening. In the first round of optimization compound 8, with a cyclopentane core, was chosen as the most promising agonist (β-arrestin recruitment EC = 20 nM and calcium mobilization EC = 740 nM). In a human neutrophil static adhesion assay, compound 8 decreased the number of adherent neutrophils in a concentration dependent manner. Further investigation led to the more rigid cycloleucines (compound 22 and 24) with improved ADME profiles and maintaining FPR2 activity. Overall, we identified novel cyclopentane urea FPR2 agonists with promising ADMET profiles and the ability to suppress the inflammatory process by inhibiting the neutrophil adhesion cascade, which indicates their anti-inflammatory and pro-resolving properties.
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http://dx.doi.org/10.1016/j.ejmech.2021.113194DOI Listing
March 2021

Arterial Delivery of VEGF-C Stabilizes Atherosclerotic Lesions.

Circ Res 2021 Jan 19;128(2):284-286. Epub 2020 Nov 19.

Institute for Cardiovascular Prevention (IPEK), Klinikum der LMU München (C.S.-R., P.L., O.S.).

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http://dx.doi.org/10.1161/CIRCRESAHA.120.317186DOI Listing
January 2021

Endotoxinemia Accelerates Atherosclerosis Through Electrostatic Charge-Mediated Monocyte Adhesion.

Circulation 2021 Jan 10;143(3):254-266. Epub 2020 Nov 10.

Institute for Cardiovascular Prevention (IPEK), LMU Munich Hospital, Germany (A.S., A.O.-G., C.W., P. Lemnitzer, J.R.V., C.P., L.P.O., J.W., Y.D., O.S.).

Background: Acute infection is a well-established risk factor of cardiovascular inflammation increasing the risk for a cardiovascular complication within the first weeks after infection. However, the nature of the processes underlying such aggravation remains unclear. Lipopolysaccharide derived from Gram-negative bacteria is a potent activator of circulating immune cells including neutrophils, which foster inflammation through discharge of neutrophil extracellular traps (NETs). Here, we use a model of endotoxinemia to link acute infection and subsequent neutrophil activation with acceleration of vascular inflammation Methods: Acute infection was mimicked by injection of a single dose of lipopolysaccharide into hypercholesterolemic mice. Atherosclerosis burden was studied by histomorphometric analysis of the aortic root. Arterial myeloid cell adhesion was quantified by intravital microscopy.

Results: Lipopolysaccharide treatment rapidly enhanced atherosclerotic lesion size by expansion of the lesional myeloid cell accumulation. Lipopolysaccharide treatment led to the deposition of NETs along the arterial lumen, and inhibition of NET release annulled lesion expansion during endotoxinemia, thus suggesting that NETs regulate myeloid cell recruitment. To study the mechanism of monocyte adhesion to NETs, we used in vitro adhesion assays and biophysical approaches. In these experiments, NET-resident histone H2a attracted monocytes in a receptor-independent, surface charge-dependent fashion. Therapeutic neutralization of histone H2a by antibodies or by in silico designed cyclic peptides enables us to reduce luminal monocyte adhesion and lesion expansion during endotoxinemia.

Conclusions: Our study shows that NET-associated histone H2a mediates charge-dependent monocyte adhesion to NETs and accelerates atherosclerosis during endotoxinemia.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914394PMC
January 2021

Co-option of Neutrophil Fates by Tissue Environments.

Cell 2020 Nov 23;183(5):1282-1297.e18. Epub 2020 Oct 23.

Kennedy Institute of Rheumatology, University of Oxford, OX3 7FY, UK.

Classically considered short-lived and purely defensive leukocytes, neutrophils are unique in their fast and moldable response to stimulation. This plastic behavior may underlie variable and even antagonistic functions during inflammation or cancer, yet the full spectrum of neutrophil properties as they enter healthy tissues remains unexplored. Using a new model to track neutrophil fates, we found short but variable lifetimes across multiple tissues. Through analysis of the receptor, transcriptional, and chromatin accessibility landscapes, we identify varying neutrophil states and assign non-canonical functions, including vascular repair and hematopoietic homeostasis. Accordingly, depletion of neutrophils compromised angiogenesis during early age, genotoxic injury, and viral infection, and impaired hematopoietic recovery after irradiation. Neutrophils acquired these properties in target tissues, a process that, in the lungs, occurred in CXCL12-rich areas and relied on CXCR4. Our results reveal that tissues co-opt neutrophils en route for elimination to induce programs that support their physiological demands.
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http://dx.doi.org/10.1016/j.cell.2020.10.003DOI Listing
November 2020

The Atlas of Inflammation Resolution (AIR).

Mol Aspects Med 2020 08 3;74:100894. Epub 2020 Sep 3.

Department of Systems Biology and Bioinformatics, University of Rostock, 18051, Rostock, Germany; Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, Stellenbosch, South Africa. Electronic address:

Acute inflammation is a protective reaction by the immune system in response to invading pathogens or tissue damage. Ideally, the response should be localized, self-limited, and returning to homeostasis. If not resolved, acute inflammation can result in organ pathologies leading to chronic inflammatory phenotypes. Acute inflammation and inflammation resolution are complex coordinated processes, involving a number of cell types, interacting in space and time. The biomolecular complexity and the fact that several biomedical fields are involved, make a multi- and interdisciplinary approach necessary. The Atlas of Inflammation Resolution (AIR) is a web-based resource capturing an essential part of the state-of-the-art in acute inflammation and inflammation resolution research. The AIR provides an interface for users to search thousands of interactions, arranged in inter-connected multi-layers of process diagrams, covering a wide range of clinically relevant phenotypes. By mapping experimental data onto the AIR, it can be used to elucidate drug action as well as molecular mechanisms underlying different disease phenotypes. For the visualization and exploration of information, the AIR uses the Minerva platform, which is a well-established tool for the presentation of disease maps. The molecular details of the AIR are encoded using international standards. The AIR was created as a freely accessible resource, supporting research and education in the fields of acute inflammation and inflammation resolution. The AIR connects research communities, facilitates clinical decision making, and supports research scientists in the formulation and validation of hypotheses. The AIR is accessible through https://air.bio.informatik.uni-rostock.de.
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http://dx.doi.org/10.1016/j.mam.2020.100894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733955PMC
August 2020

WITHDRAWN: The Atlas of Inflammation Resolution (AIR).

Mol Aspects Med 2020 Aug 29:100893. Epub 2020 Aug 29.

Department of Systems Biology and Bioinformatics, University of Rostock, 18051, Rostock, Germany; Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, Stellenbosch, South Africa. Electronic address:

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http://dx.doi.org/10.1016/j.mam.2020.100893DOI Listing
August 2020

Meta-Analysis of Leukocyte Diversity in Atherosclerotic Mouse Aortas.

Circ Res 2020 Jul 16;127(3):402-426. Epub 2020 Jul 16.

La Jolla Institute for Immunology, CA (C.C.H., Y.G., H.Q.D., K.L.).

The diverse leukocyte infiltrate in atherosclerotic mouse aortas was recently analyzed in 9 single-cell RNA sequencing and 2 mass cytometry studies. In a comprehensive meta-analysis, we confirm 4 known macrophage subsets-resident, inflammatory, interferon-inducible cell, and Trem2 (triggering receptor expressed on myeloid cells-2) foamy macrophages-and identify a new macrophage subset resembling cavity macrophages. We also find that monocytes, neutrophils, dendritic cells, natural killer cells, innate lymphoid cells-2, and CD (cluster of differentiation)-8 T cells form prominent and separate immune cell populations in atherosclerotic aortas. Many CD4 T cells express IL (interleukin)-17 and the chemokine receptor CXCR (C-X-C chemokine receptor)-6. A small number of regulatory T cells and T helper 1 cells is also identified. Immature and naive T cells are present in both healthy and atherosclerotic aortas. Our meta-analysis overcomes limitations of individual studies that, because of their experimental approach, over- or underrepresent certain cell populations. Mass cytometry studies demonstrate that cell surface phenotype provides valuable information beyond the cell transcriptomes. The present analysis helps resolve some long-standing controversies in the field. First, Trem2 foamy macrophages are not proinflammatory but interferon-inducible cell and inflammatory macrophages are. Second, about half of all foam cells are smooth muscle cell-derived, retaining smooth muscle cell transcripts rather than transdifferentiating to macrophages. Third, , which had been considered specific for platelets and megakaryocytes, is also prominently expressed in the main population of resident vascular macrophages. Fourth, a new type of resident macrophage shares transcripts with cavity macrophages. Finally, the discovery of a prominent innate lymphoid cell-2 cluster links the single-cell RNA sequencing work to recent flow cytometry data suggesting a strong atheroprotective role of innate lymphoid cells-2. This resolves apparent discrepancies regarding the role of T helper 2 cells in atherosclerosis based on studies that predated the discovery of innate lymphoid cells-2 cells.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.316903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371244PMC
July 2020

Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability.

Circ Res 2020 Aug 17;127(6):811-823. Epub 2020 Jun 17.

From the Institute for Stroke and Dementia Research, University Hospital (Y.A., T.A.C.-J., Y.B., L.L.Y., M.P., O.E.B., S.R., K.T., G.Y., M.S., N.Z., S.T., Y.H., M.S., R.M., C.H., A.L., J.B., M.D.), Ludwig-Maximilians-University, Munich, Germany.

Rationale: Arterial inflammation manifested as atherosclerosis is the leading cause of mortality worldwide. Genome-wide association studies have identified a prominent role of HDAC (histone deacetylase)-9 in atherosclerosis and its clinical complications including stroke and myocardial infarction.

Objective: To determine the mechanisms linking HDAC9 to these vascular pathologies and explore its therapeutic potential for atheroprotection.

Methods And Results: We studied the effects of on features of plaque vulnerability using bone marrow reconstitution experiments and pharmacological targeting with a small molecule inhibitor in hyperlipidemic mice. We further used 2-photon and intravital microscopy to study endothelial activation and leukocyte-endothelial interactions. We show that hematopoietic deficiency reduces lesional macrophage content while increasing fibrous cap thickness thus conferring plaque stability. We demonstrate that HDAC9 binds to IKK (inhibitory kappa B kinase)-α and β, resulting in their deacetylation and subsequent activation, which drives inflammatory responses in both macrophages and endothelial cells. Pharmacological inhibition of HDAC9 with the class IIa HDAC inhibitor TMP195 attenuates lesion formation by reducing endothelial activation and leukocyte recruitment along with limiting proinflammatory responses in macrophages. Transcriptional profiling using RNA sequencing revealed that TMP195 downregulates key inflammatory pathways consistent with inhibitory effects on IKKβ. TMP195 mitigates the progression of established lesions and inhibits the infiltration of inflammatory cells. Moreover, TMP195 diminishes features of plaque vulnerability and thereby enhances plaque stability in advanced lesions. Ex vivo treatment of monocytes from patients with established atherosclerosis reduced the production of inflammatory cytokines including IL (interleukin)-1β and IL-6.

Conclusions: Our findings identify HDAC9 as a regulator of atherosclerotic plaque stability and IKK activation thus providing a mechanistic explanation for the prominence of HDAC9 as a vascular risk locus in genome-wide association studies. Its therapeutic inhibition may provide a potent lever to alleviate vascular inflammation. Graphical Abstract: A graphical abstract is available for this article.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.316743DOI Listing
August 2020

Agrin Promotes Coordinated Therapeutic Processes Leading to Improved Cardiac Repair in Pigs.

Circulation 2020 Sep 8;142(9):868-881. Epub 2020 Jun 8.

The Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel (K.B.U., E.B., D.K., R.C.-R., E.T.).

Background: Ischemic heart diseases are leading causes of death and reduced life quality worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a large number of patients with MI develop chronic heart failure over time. We previously reported that a fragment of the extracellular matrix protein agrin promotes cardiac regeneration after MI in adult mice.

Methods: To test the therapeutic potential of agrin in a preclinical porcine model, we performed ischemia-reperfusion injuries using balloon occlusion for 60 minutes followed by a 3-, 7-, or 28-day reperfusion period.

Results: We demonstrated that local (antegrade) delivery of recombinant human agrin to the infarcted pig heart can target the affected regions in an efficient and clinically relevant manner. A single dose of recombinant human agrin improved heart function, infarct size, fibrosis, and adverse remodeling parameters 28 days after MI. Short-term MI experiments along with complementary murine studies revealed myocardial protection, improved angiogenesis, inflammatory suppression, and cell cycle reentry as agrin's mechanisms of action.

Conclusions: A single dose of agrin is capable of reducing ischemia-reperfusion injury and improving heart function, demonstrating that agrin could serve as a therapy for patients with acute MI and potentially heart failure.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.045116DOI Listing
September 2020

Lack of Proteinase 3 Stabilizes Advanced Atherosclerotic Lesions.

Thromb Haemost 2020 06 13;120(6):994-997. Epub 2020 May 13.

Institute for Cardiovascular Prevention, LMU Munich, Munich, Germany.

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http://dx.doi.org/10.1055/s-0040-1710316DOI Listing
June 2020

Neutrophil Extracellular Traps Participate in Cardiovascular Diseases: Recent Experimental and Clinical Insights.

Circ Res 2020 04 23;126(9):1228-1241. Epub 2020 Apr 23.

Institute of Cardiovascular Prevention, Department of Medicine, Ludwig-Maximilians-University Munich, Germany (Y.D., O.S.).

Neutrophil extracellular traps (NETs) have recently emerged as a newly recognized contributor to venous and arterial thrombosis. These strands of DNA extruded by activated or dying neutrophils, decorated with various protein mediators, become solid-state reactors that can localize at the critical interface of blood with the intimal surface of diseased arteries and propagate and amplify the regional injury. NETs thus furnish a previously unsuspected link between inflammation, innate immunity, thrombosis, oxidative stress, and cardiovascular diseases. In response to disease-relevant stimuli, neutrophils undergo a specialized series of reactions that culminate in NET formation. DNA derived from either nuclei or mitochondria can contribute to NET formation. The DNA liberated from neutrophils forms a reticular mesh that resembles morphologically a net, rendering the acronym NETs particularly appropriate. The DNA backbone of NETs not only presents intrinsic neutrophil proteins (eg, MPO [myeloperoxidase] and various proteinases) but can gather other proteins found in blood (eg, tissue factor procoagulant). This review presents current concepts of neutrophil biology, the triggers to and mechanisms of NET formation, and the contribution of NETs to atherosclerosis and to thrombosis. We consider the use of markers of NETs in clinical studies. We aim here to integrate critically the experimental literature with the growing body of clinical information regarding NETs.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.315931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185047PMC
April 2020

Thrombo-Inflammation in Cardiovascular Disease: An Expert Consensus Document from the Third Maastricht Consensus Conference on Thrombosis.

Thromb Haemost 2020 Apr 14;120(4):538-564. Epub 2020 Apr 14.

Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany; Haemostasis Research Unit, University College London, London, United Kingdom.

Thrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on Thrombosis assembled basic, translational, and clinical scientists to discuss the origin and potential consequences of thrombo-inflammation in the etiology, diagnostics, and management of patients with cardiovascular disease, including myocardial infarction, stroke, and peripheral artery disease. This article presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following topics: (1) challenges of the endothelial cell barrier; (2) circulating cells and thrombo-inflammation, focused on platelets, neutrophils, and neutrophil extracellular traps; (3) procoagulant mechanisms; (4) arterial vascular changes in atherogenesis; attenuating atherosclerosis and ischemia/reperfusion injury; (5) management of patients with arterial vascular disease; and (6) pathogenesis of venous thrombosis and late consequences of venous thromboembolism.
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http://dx.doi.org/10.1055/s-0040-1708035DOI Listing
April 2020

Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases.

Cell Mol Immunol 2020 Mar 20. Epub 2020 Mar 20.

ModiQuest B.V., Oss, The Netherlands.

Excessive release of neutrophil extracellular traps (NETs) is associated with disease severity and contributes to tissue injury, followed by severe organ damage. Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. Here, we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody (tACPA) has broad therapeutic potential. Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology, including inflammatory arthritis (IA), pulmonary fibrosis, inflammatory bowel disease and sepsis. We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention, whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects. Because citrullinated histones are generated during NET release, we investigated the ability of tACPA to inhibit NET formation. tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human disease-related stimuli. Moreover, tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo, which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA. To our knowledge, we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases, as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner.
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http://dx.doi.org/10.1038/s41423-020-0381-3DOI Listing
March 2020

Chemokines and galectins form heterodimers to modulate inflammation.

EMBO Rep 2020 04 21;21(4):e47852. Epub 2020 Feb 21.

Department of Biochemistry, Molecular Biology & Biophysics, Health Sciences Center, University of Minnesota, Minneapolis, MN, USA.

Chemokines and galectins are simultaneously upregulated and mediate leukocyte recruitment during inflammation. Until now, these effector molecules have been considered to function independently. Here, we tested the hypothesis that they form molecular hybrids. By systematically screening chemokines for their ability to bind galectin-1 and galectin-3, we identified several interacting pairs, such as CXCL12 and galectin-3. Based on NMR and MD studies of the CXCL12/galectin-3 heterodimer, we identified contact sites between CXCL12 β-strand 1 and Gal-3 F-face residues. Mutagenesis of galectin-3 residues involved in heterodimer formation resulted in reduced binding to CXCL12, enabling testing of functional activity comparatively. Galectin-3, but not its mutants, inhibited CXCL12-induced chemotaxis of leukocytes and their recruitment into the mouse peritoneum. Moreover, galectin-3 attenuated CXCL12-stimulated signaling via its receptor CXCR4 in a ternary complex with the chemokine and receptor, consistent with our structural model. This first report of heterodimerization between chemokines and galectins reveals a new type of interaction between inflammatory mediators that can underlie a novel immunoregulatory mechanism in inflammation. Thus, further exploration of the chemokine/galectin interactome is warranted.
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http://dx.doi.org/10.15252/embr.201947852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132340PMC
April 2020

Neutrophils as regulators of cardiovascular inflammation.

Nat Rev Cardiol 2020 06 29;17(6):327-340. Epub 2020 Jan 29.

Institute for Cardiovascular Prevention (IPEK), Klinikum LMU Munich, Munich, Germany.

Neutrophils have traditionally been viewed as bystanders or biomarkers of cardiovascular disease. However, studies in the past decade have demonstrated the important functions of neutrophils during cardiovascular inflammation and repair. In this Review, we discuss the influence of traditional and novel cardiovascular risk factors on neutrophil production and function. We then appraise the current knowledge of the contribution of neutrophils to the different stages of atherosclerosis, including atherogenesis, plaque destabilization and plaque erosion. In the context of cardiovascular complications of atherosclerosis, we highlight the dichotomous role of neutrophils in pathogenic and repair processes in stroke, heart failure, myocardial infarction and neointima formation. Finally, we emphasize how detailed knowledge of neutrophil functions in cardiovascular homeostasis and disease can be used to generate therapeutic strategies to target neutrophil numbers, functional status and effector mechanisms.
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http://dx.doi.org/10.1038/s41569-019-0326-7DOI Listing
June 2020

CX3CR1-fractalkine axis drives kinetic changes of monocytes in fibrotic interstitial lung diseases.

Eur Respir J 2020 02 20;55(2). Epub 2020 Feb 20.

Comprehensive Pneumology Center, Ludwig-Maximilians University (LMU), University Hospital Grosshadern, and Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany

Circulating immune cell populations have been shown to contribute to interstitial lung disease (ILD). In this study, we analysed circulating and lung resident monocyte populations, and assessed their phenotype and recruitment from the blood to the lung in ILD. Flow cytometry analysis of blood samples for quantifying circulating monocytes was performed in 105 subjects: 83 with ILD (n=36, n=28 and n=19 for nonspecific interstitial pneumonia, hypersensitivity pneumonitis and connective-tissue disease-associated ILD, respectively), as well as 22 controls. Monocyte localisation and abundance were assessed using immunofluorescence and flow cytometry of lung tissue. Monocyte populations were cultured either alone or with endothelial cells to assess fractalkine-dependent transmigration pattern. We show that circulating classical monocytes (CM) were increased in ILD compared with controls, while nonclassical monocytes (NCM) were decreased. CM abundance correlated inversely with lung function, while NCM abundance correlated positively. Both CCL2 and CX3CL1 concentrations were increased in plasma and lungs of ILD patients. Fractalkine co-localised with ciliated bronchial epithelial cells, thereby creating a chemoattractant gradient towards the lung. Fractalkine enhanced endothelial transmigration of NCM in ILD samples only. Immunofluorescence, as well as flow cytometry, showed an increased presence of NCM in fibrotic niches in ILD lungs. Moreover, NCM in the ILD lungs expressed increased CX3CR1, M2-like and phagocytic markers. Taken together, our data support that in ILD, fractalkine drives the migration of CX3CR1 NCM to the lungs, thereby perpetuating the local fibrotic process.
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http://dx.doi.org/10.1183/13993003.00460-2019DOI Listing
February 2020

Artery-Associated Sympathetic Innervation Drives Rhythmic Vascular Inflammation of Arteries and Veins.

Circulation 2019 09 12;140(13):1100-1114. Epub 2019 Aug 12.

Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-University Munich, BioMedical Centre, Planegg-Martinsried, Germany (A.d.J., L.M.I., R.P., C.-S.C., G.Z., D.D., M.E.T.H., S.M.H., E.M., C.A.R., C.S.).

Background: The incidence of acute cardiovascular complications is highly time-of-day dependent. However, the mechanisms driving rhythmicity of ischemic vascular events are unknown. Although enhanced numbers of leukocytes have been linked to an increased risk of cardiovascular complications, the role that rhythmic leukocyte adhesion plays in different vascular beds has not been studied.

Methods: We evaluated leukocyte recruitment in vivo by using real-time multichannel fluorescence intravital microscopy of a tumor necrosis factor-α-induced acute inflammation model in both murine arterial and venous macrovasculature and microvasculature. These approaches were complemented with genetic, surgical, and pharmacological ablation of sympathetic nerves or adrenergic receptors to assess their relevance for rhythmic leukocyte adhesion. In addition, we genetically targeted the key circadian clock gene (also known as ) in a lineage-specific manner to dissect the importance of oscillations in leukocytes and components of the vessel wall in this process.

Results: In vivo quantitative imaging analyses of acute inflammation revealed a 24-hour rhythm in leukocyte recruitment to arteries and veins of the mouse macrovasculature and microvasculature. Unexpectedly, although in arteries leukocyte adhesion was highest in the morning, it peaked at night in veins. This phase shift was governed by a rhythmic microenvironment and a vessel type-specific oscillatory pattern in the expression of promigratory molecules. Differences in cell adhesion molecules and leukocyte adhesion were ablated when disrupting sympathetic nerves, demonstrating their critical role in this process and the importance of β-adrenergic receptor signaling. Loss of the core clock gene in leukocytes, endothelial cells, or arterial mural cells affected the oscillations in a vessel type-specific manner. Rhythmicity in the intravascular reactivity of adherent leukocytes resulted in increased interactions with platelets in the morning in arteries and in veins at night with a higher predisposition to acute thrombosis at different times as a consequence.

Conclusions: Together, our findings point to an important and previously unrecognized role of artery-associated sympathetic innervation in governing rhythmicity in vascular inflammation in both arteries and veins and its potential implications in the occurrence of time-of-day-dependent vessel type-specific thrombotic events.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.040232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756975PMC
September 2019

Myeloid-Specific Deletion of the AMPKα2 Subunit Alters Monocyte Protein Expression and Atherogenesis.

Int J Mol Sci 2019 Jun 19;20(12). Epub 2019 Jun 19.

Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, 60596 Frankfurt am Main, Germany.

The AMP-activated protein kinase (AMPK) is an energy sensing kinase that is activated by a drop in cellular ATP levels. Although several studies have addressed the role of the AMPKα1 subunit in monocytes and macrophages, little is known about the α2 subunit. The aim of this study was to assess the consequences of AMPKα2 deletion on protein expression in monocytes/macrophages, as well as on atherogenesis. A proteomics approach was applied to bone marrow derived monocytes from wild-type mice versus mice specifically lacking AMPKα2 in myeloid cells (AMPKα2 mice). This revealed differentially expressed proteins, including methyltransferases. Indeed, AMPKα2 deletion in macrophages increased the ratio of S-adenosyl methionine to S-adenosyl homocysteine and increased global DNA cytosine methylation. Also, methylation of the vascular endothelial growth factor and matrix metalloproteinase-9 (MMP9) genes was increased in macrophages from AMPKα2 mice, and correlated with their decreased expression. To link these findings with an in vivo phenotype, AMPKα2 mice were crossed onto the ApoE background and fed a western diet. ApoExAMPKα2 mice developed smaller atherosclerotic plaques than their ApoExα2 littermates, that contained fewer macrophages and less MMP9 than plaques from ApoExα2 littermates. These results indicate that the AMPKα2 subunit in myeloid cells influences DNA methylation and thus protein expression and contributes to the development of atherosclerotic plaques.
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http://dx.doi.org/10.3390/ijms20123005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627871PMC
June 2019

Tick saliva protein Evasin-3 modulates chemotaxis by disrupting CXCL8 interactions with glycosaminoglycans and CXCR2.

J Biol Chem 2019 08 24;294(33):12370-12379. Epub 2019 Jun 24.

Department of Biochemistry, University of Maastricht, Cardiovascular Research Institute Maastricht, 6229 ER, Maastricht, The Netherlands. Electronic address:

Chemokines are a group of chemotaxis proteins that regulate cell trafficking and play important roles in immune responses and inflammation. Ticks are blood-sucking parasites that secrete numerous immune-modulatory agents in their saliva to evade host immune responses. Evasin-3 is a small salivary protein that belongs to a class of chemokine-binding proteins isolated from the brown dog tick, Evasin-3 has been shown to have a high affinity for chemokines CXCL1 and CXCL8 and to diminish inflammation in mice. In the present study, solution NMR spectroscopy was used to investigate the structure of Evasin-3 and its CXCL8-Evasin-3 complex. Evasin-3 is found to disrupt the glycosaminoglycan-binding site of CXCL8 and inhibit the interaction of CXCL8 with CXCR2. Structural data were used to design two novel CXCL8-binding peptides. The linear tEv3 17-56 and cyclic tcEv3 16-56 dPG Evasin-3 variants were chemically synthesized by solid-phase peptide synthesis. The affinity of these newly synthesized variants to CXCL8 was measured by surface plasmon resonance biosensor analysis. The values of tEv3 17-56 and tcEv3 16-56 dPG were 27 and 13 nm, respectively. Both compounds effectively inhibited CXCL8-induced migration of polymorphonuclear neutrophils. The present results suggest utility of synthetic Evasin-3 variants as scaffolds for designing and fine-tuning new chemokine-binding agents that suppress immune responses and inflammation.
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http://dx.doi.org/10.1074/jbc.RA119.008902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699855PMC
August 2019

Heparinoid sevuparin inhibits -induced vascular leak through neutralizing neutrophil-derived proteins.

FASEB J 2019 09 19;33(9):10443-10452. Epub 2019 Jun 19.

Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.

Acute lung injury (ALI) and respiratory distress can develop as a consequence of sepsis with pathogens such as group A (GAS). In the pathogenesis of sepsis-associated ALI, endothelial barrier disruption brought on by phagocyte activation is considered a causative factor. Here, we find that sevuparin, a heparinoid with low anticoagulant activity, prevents neutrophil-induced lung plasma leakage in a murine model of systemic inflammation evoked by heat-killed GAS (hkGAS). Furthermore, using human neutrophils and endothelial cell monolayers, we demonstrate that sevuparin inhibits hkGAS-induced endothelial barrier disruption by neutralizing the activity of neutrophil-derived proteins. By mass spectrometry of neutrophil secretion, we identify proteins, including serprocidins, S100 proteins, and histone H4, that interact with sevuparin and that are responsible for the disruptive effect on endothelial integrity. Collectively, our results demonstrate the critical role of neutrophil-derived proteins in vascular hyperpermeability caused by GAS and suggest sevuparin as a potential therapeutic in acute neutrophilic inflammation.-Rasmuson, J., Kenne, E., Wahlgren, M., Soehnlein, O., Lindbom, L. Heparinoid sevuparin inhibits -induced vascular leak through neutralizing neutrophil-derived proteins.
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http://dx.doi.org/10.1096/fj.201900627RDOI Listing
September 2019

Pro-Angiogenic Macrophage Phenotype to Promote Myocardial Repair.

J Am Coll Cardiol 2019 06;73(23):2990-3002

Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität Munich, Munich, Germany; Deutsches Zentrum für Herz-Kreislaufforschung (DZHK), partner site Munich Heart Alliance, Munich, Germany; Department of Physiology and Pharmacology (FyFa) and Department of Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Background: Heart failure following myocardial infarction (MI) remains one of the major causes of death worldwide, and its treatment is a crucial challenge of cardiovascular medicine. An attractive therapeutic strategy is to stimulate endogenous mechanisms of myocardial regeneration.

Objectives: This study evaluates the potential therapeutic treatment with annexin A1 (AnxA1) to induce cardiac repair after MI.

Methods: AnxA1 knockout (AnxA1) and wild-type mice underwent MI induced by ligation of the left anterior descending coronary artery. Cardiac functionality was assessed by longitudinal echocardiographic measurements. Histological, fluorescence-activated cell sorting, dot blot analysis, and in vitro/ex vivo studies were used to assess the myocardial neovascularization, macrophage content, and activity in response to AnxA1.

Results: AnxA1 mice showed a reduced cardiac functionality and an expansion of proinflammatory macrophages in the ischemic area. Cardiac macrophages from AnxA1 mice exhibited a dramatically reduced ability to release the proangiogenic mediator vascular endothelial growth factor (VEGF)-A. However, AnxA1 treatment enhanced VEGF-A release from cardiac macrophages, and its delivery in vivo markedly improved cardiac performance. The positive effect of AnxA1 treatment on cardiac performance was abolished in wild-type mice transplanted with bone marrow derived from Cxcr1creVegf or in mice depleted of macrophages. Similarly, cardioprotective effects of AnxA1 were obtained in pigs in which full-length AnxA1 was overexpressed by use of a cardiotropic adeno-associated virus.

Conclusions: AnxA1 has a direct action on cardiac macrophage polarization toward a pro-angiogenic, reparative phenotype. AnxA1 stimulated cardiac macrophages to release high amounts of VEGF-A, thus inducing neovascularization and cardiac repair.
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http://dx.doi.org/10.1016/j.jacc.2019.03.503DOI Listing
June 2019

Biological Roles of Neutrophil-Derived Granule Proteins and Cytokines.

Trends Immunol 2019 07 30;40(7):648-664. Epub 2019 May 30.

Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Institute for Cardiovascular Prevention (IPEK), Klinikum der LMU, München, Germany; German Centre for Cardiovascular Research (DZHK), Partner site, Munich, Germany. Electronic address:

Neutrophils, the most abundant white blood cells in human circulation, entertain intense interactions with other leukocyte subsets, platelets, and stromal cells. Molecularly, such interactions are typically communicated through proteins generated during granulopoiesis, stored in granules, or produced on demand. Here, we provide an overview of the mammalian regulation of granule protein production in the bone marrow and the de novo synthesis of cytokines by neutrophils recruited to tissues. In addition, we discuss some of the known biological roles of these protein messengers, and how neutrophil-borne granule proteins and cytokines can synergize to modulate inflammation and tumor development. Decoding the neutrophil interactome is important for therapeutically neutralizing individual proteins to putatively dampen inflammation, or for delivering modified neutrophil-borne proteins to boost host defense.
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http://dx.doi.org/10.1016/j.it.2019.05.003DOI Listing
July 2019

Neutrophil Research, Quo Vadis?

Authors:
Oliver Soehnlein

Trends Immunol 2019 07 24;40(7):561-564. Epub 2019 May 24.

Department of Physiology and Pharmacology and Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Institute for Cardiovascular Prevention (IPEK), Klinikum der LMU München, Munich, Germany; German Centre for Cardiovascular Research (DZHK), Partner site Munich, Munich, Germany. Electronic address:

In recent years, great progress has been made to understand how neutrophils contribute to homeostatic regulation, tumor progression, and chronic inflammation. Here, I highlight a few salient basic questions to be addressed in the field. Ideally, future investigations along these lines can contribute to identifying possible means of therapeutically interfering with neutrophil effector functions to fine-tune innate immunity.
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http://dx.doi.org/10.1016/j.it.2019.04.011DOI Listing
July 2019